Anti-prolactin receptor antibody formulations

ABSTRACT

Provided are a wide concentration range, especially high concentration, substantially salt-free anti-prolactin receptor antibody formulations that are substantially isosmotic and of low viscosity.

BACKGROUND

The present disclosure relates generally to a wide concentration rangeof anti-prolactin receptor antibody formulations that are substantiallyisosmotic and of low viscosity, including formulations that are usefulfor subcutaneous and general injection administration.

Prolactin (PRL) is a polypeptide hormone composed of 199 amino acids.PRL belongs to the growth hormone (GH), placental lactogen (PL) familyof polypeptide hormones and is synthesized in lactotroph cells of thepituitary and in several extrapituitary tissues such as lymphocytes,mammary epithelial cells, the myometrium, and the prostate. Twodifferent promoters regulate pituitary and extrapituitary PRL synthesis(BioEssays 28:1051-1055 (2006)).

PRL binds to the PRL receptor (PRLR), a single transmembrane receptorbelonging to the class 1 cytokine receptor superfamily (EndocrineReviews 19:225-268 (1998)). PRLR exists in three different isoforms, theshort, the long, and the intermediate form that can be distinguished bythe length of their cytoplasmic tails. Upon ligand binding, a sequentialprocess leads to PRLR activation. PRL interacts via its binding site 1with one PRLR molecule and then attracts via its binding site 2 a secondreceptor molecule leading to an active dimer of PRLRs.

PRLR dimerization leads to the predominant activation of the JAK/STAT(Janus Kinase/Signal transducers and activators of transcription)pathway. Upon receptor dimerization, JAKs (predominantly JAK2)associated with the receptor, transphosphorylate and activate eachother. In addition the PRLR is also phosphorylated and can bind toSH2-domain containing proteins such as STATs. Receptor bound STATs aresubsequently phosphorylated, dissociate from the receptor andtranslocate to the nucleus where they stimulate transcription of targetgenes. In addition, activation of the Ras-Raf-MAPK pathway andactivation of the cytoplasmic src kinase by PRLRs have been described(for review Endocrine Reviews 19: 225-268 (1998)).

The role of PRLR-mediated signalling has been investigated in thecontext of the benign disease endometriosis. In one study the expressionpattern of the PRLR in endometriotic samples and eutopic endometriumfrom endometriosis patients was analysed (Acta Obstet Gynecol Scand81:5-10, 2002) during the mid-late proliferative phase of the menstrualcycle. It was demonstrated that the PRLR mRNA was present in the eutopicendometrium in 79% of the analysed endometriosis patients, whereas itwas absent in the endometriotic lesions in 86% of the endometriosispatients. These data suggested a possible differential regulation ofPRLR expression between normal and endometriotic tissue. However, fromthese expression data it cannot be concluded that inhibition of the PRLRmight represent a suitable endometriosis therapy—especially since thePRLR was not found to be expressed in the endometriotic lesions (ActaObstet Gynecol Scand 81:5-10 (2002)).

Antibodies that are directed against prolactin receptor (PRLR),including anti-PRLR monoclonal antibodies (aPRLR mAbs), are beingdeveloped in an effort to block PRLR function. One such aPRLR mAb is anIgG2 anti-PRLR mAb that is being developed for the non-hormonaltreatment of endometriosis patients.

Antibodies may be administrated to patients via intravenous,intramuscular, and/or subcutaneous injection. To ensure patientcompliance, it is desirable that intramuscular and subcutaneousinjection dosage forms be isotonic and include small injection volumes(<2 ml per injection site). To reduce injection volume, and to providean effective dose, antibodies are often administered with a wideconcentration range, from 1 mg/ml to 150 mg/mL, including highconcentrations within the range of 20 mg/ml to 150 mg/ml.

While both liquid and lyophilized dosage forms are used for currentlymarketed antibody drug products, lyophilized forms are more frequentlyused for antibody drug products having high protein concentrations. Ahigh concentration antibody formulation may present many challenges informulation development, especially for liquid formulation. Forformulations in which the antibody concentration is near its apparentsolubility limit, phase separation can occur through precipitation,gelation, and/or crystallization. At high protein concentration, thestability of an antibody can become problematic due to the formation ofsoluble and insoluble protein-protein aggregates. Highly concentratedantibody formulations are frequently highly viscous, which presentsdifficulties for processing, such as ultrafiltration and sterilefiltration, and for injection of the dosage solution. And at highantibody concentrations, which are desirable for formulations intendedfor intramuscular or subcutaneous administration, proportionally highconcentrations of stabilizers, such as sucrose and sodium chloride, arerequired to achieve long-term protein stability. The resultinghypertonic solutions often cause injection pain due to tissue damage.Therefore, it is often desirable to balance the amount of stabilizersfor stability and osmolality of the high protein concentrationformulation.

SUMMARY

The present disclosure provides liquid and lyophilized anti-PRLRantibody formulations with a wide range of anti-PRLR antibodyconcentrations, which are substantially isotonic and low viscosity andthat contain substantially no salt other than an organic salt or aninorganic salt that is used to buffer the formulation.

The anti-PRLR antibody formulations presented herein contain from about0 mM to about 70 mM histidine; from about 50 ppm to about 300 ppm of anon-ionic surfactant such as, for example, polysorbate (Tween®) 80and/or polysorbate (Tween®) 20; from about 34 mM to about 292 mM of asugar or sugar alcohol such as, for example, mannitol, dextrose,glucose, trehalose, and/or sucrose; from about 0 mM to about 50 mMarginine; from about 0 mM to about 50 mM lysine; from about 0 mM toabout 270 mM glycine or alanine; from about 0 mM to about 10 mMmethionine; and from about 1 mg/ml to about 150 mg/ml of an anti-PRLRantibody, including an aPRLR-specific IgG2 monoclonal antibody (mAb) ata pH from about pH 5.0 to about pH 6.5.

Each of the presently disclosed antibody formulations containssubstantially no salt other than an organic salt or an inorganic saltthat is used to buffer the formulation. This permits the addition ofalternative stabilizers to maintain the isosmoticity of the formulation(i.e., osmolality ranging from about 240 mmol/kg to about 380 mmol/kg),which thereby promotes a higher degree of patient compliance.

Each of the presently disclosed antibody formulations has a lowviscosity ranging from about 1 to about 8 mPa-S at 22° C.-23° C., whichpromotes ease of processing such as, for example, improvedultrafiltration and sterile filtration as well as injection of theantibody formulation through a syringe needle during administration.

The formulations disclosed herein stabilize antibodies, in particularanti-PRLR antibodies including anti-PRLR IgG2 antibodies, at highprotein concentrations in liquid form or in lyophilized form.

DESCRIPTION OF VARIOUS EMBODIMENTS

As described above, the present disclosure provides anti-PRLR antibodyformulations that stabilize the anti-PRLR antibody in a wide range ofconcentrations in liquid form or in lyophilized form at intended storageconditions. The formulations described herein include one or morepharmaceutically acceptable excipients or stabilizers, and are containedin buffered media at a suitable pH and are substantially isosmotic withphysiological fluids. For systemic administration, injection is onepossible route of administration, including intramuscular, intravenous,intraperitoneal, and subcutaneous for injection.

Because of their low viscosity, the presently disclosed anti-PRLRantibody formulations can be conveniently processed via, for example,ultrafiltration and sterile filtration and can be administered to apatient via injection, including both intravenous and subcutaneousinjection. Moreover, because they are substantially isosmotic, thepresently disclosed anti-PRLR antibody formulations reduce tissue damageor other adverse physiologic effects and thereby achieving favorablepatient tolerance and increased patient compliance.

The formulations described herein are characterized by the substantialabsence of added salt other than an organic salt or an inorganic saltthat is used to buffer the formulation, which provides the flexibilityfor increasing the concentrations of other stabilizers, such as sucrose,while maintaining the osmolality of the formulation for improved in vivotolerability and, consequently, increased patient compliance. Moreover,the low viscosity of the presently described formulations permitsconvenient processing, including ultrafiltration and sterile filtration,and injection of the drug product solution through the needle.

For the purpose of interpreting this specification, the followingdefinitions will apply. In the event that any definition set forth belowconflicts with the usage of that word in any other document, includingany document incorporated herein by reference, the definition set forthbelow shall always control for purposes of interpreting thisspecification and its associated claims unless a contrary meaning isclearly intended (for example in the document where the term isoriginally used).

Whenever appropriate, terms used in the singular also will include theplural and vice versa. The use of “a” herein means “one or more” unlessstated otherwise or where the use of “one or more” is clearlyinappropriate. The use of “or” means “and/or” unless stated otherwise.The use of “comprise,” “comprises,” “comprising,” “include,” “includes,”and “including” are interchangeable and not intended to be limiting. Theterm “such as” also is not intended to be limiting. For example, theterm “including” shall mean “including, but not limited to.”Furthermore, where the description of one or more embodiments uses theterm “comprising,” those skilled in the art would understand that, insome specific instances, the embodiment or embodiments can bealternatively described using the language “consisting essentially of”and/or “consisting of”

As used herein, the term “viscosity” refers to the resistance of aliquid formulation to flow, such as when injected through a syringeneedle during administration to a patient. Viscosity measurements can bedone by a cone and plate technique with a Peltier element set at adefined temperature, such as 22° C.-23° C. as described herein.Typically, a well-defined shear stress gradient is applied to the liquidformulation and the resulting shear rate is measured. The viscosity isthe ratio of the shear stress to the shear rate. As used herein,viscosity is expressed in units of mPa-S at 22° C.-23° C. wherein 1mPa-S=1 cP. The high concentration, low viscosity, substantiallyisosmotic formulations disclosed herein are typically characterized byhaving a viscosity ranging from 1 to 8 mPa-S at 22° C.-23° C.

As used herein, the term “osmolality” refers to a measure of soluteconcentration, defined as the number of mmole of solute per kg ofsolution. A desired level of osmolality can be achieved by the additionof one or more stabilizer such as a sugar or a sugar alcohol includingmannitol, dextrose, glucose, trehalose, and/or sucrose. Additionalstabilizers that are suitable for providing osmolality are described inreferences such as the handbook of Pharmaceutical Excipients (FourthEdition, Royal Pharmaceutical Society of Great Britain, Science &Practice Publishers) or Remington: The Science and Practice of Pharmacy(Nineteenth Edition, Mack Publishing Company).

As used herein, the term “about” refers to +/−10% of the unit valueprovided. As used herein, the term “substantially” refers to thequalitative condition of exhibiting a total or approximate degree of acharacteristic or property of interest. One of ordinary skill in thebiological arts will understand that biological and chemical phenomenararely, if ever, achieve or avoid an absolute result because of the manyvariables that affect testing, production, and storage of biological andchemical compositions and materials, and because of the inherent errorin the instruments and equipment used in the testing, production, andstorage of biological and chemical compositions and materials. The termsubstantially is therefore used herein to capture the potential lack ofcompleteness inherent in many biological and chemical phenomena.

As used herein, the terms “isosmotic” and “isotonic” are usedinterchangeably with the terms “substantially isosmotic,” and“substantially isotonic” and refer to formulations characterized byhaving an osmotic pressure that is the same as or at least substantiallyequivalent to the osmotic pressure of another solution, which isachieved by formulations wherein the total concentration of solutes,including both permeable and impermeable solutes, in the formulation arethe same as or at least substantially equivalent to the total number ofsolutes in another solution. Thus, while it will be appreciated by thoseof skill in the art that “isosmotic” and “isotonic” formulations thatare used for in vivo administration generally have an osmolality rangingfrom about 270 mmol/kg to about 310 mmol/kg, in the context of the highconcentration, low viscosity formulations of the present disclosure, theterms “isosmotic,” “isotonic,” “substantially isosmotic,” and“substantially isotonic” are used interchangeably to refer toformulations having an osmolality ranging from about 240 mmol/kg toabout 380 mmol/kg, or from about 270 mmol/kg to about 370 mmol/kg, orfrom about 300 mmol/kg to about 330 mmol/kg.

The presently disclosed high concentration, low viscosity, substantiallyisosmotic anti-PRLR antibody formulations contain from about 0 mM toabout 70 mM histidine; from about 50 ppm to about 300 ppm of a non-ionicsurfactant such as, for example, polysorbate (Tween®) 80 and/orpolysorbate (Tween®) 20; from about 34 mM to about 292 mM of a sugar orsugar alcohol, such as, for example, mannitol, dextrose, glucose,trehalose, and/or sucrose; from about 0 mM to about 50 mM arginine; fromabout 0 mM to about 50 mM lysine; from about 0 mM to about 270 mMglycine or alanine; from about 0 mM to about 10 mM methionine; and fromabout 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody at a pH fromabout pH 5.0 to about pH 6.5. The formulations disclosed herein exhibita viscosity ranging from about 1 to about 8 mPa-S at 22° C.-23° C. andosmolality ranging from about 240 to about 380 mmol/kg.

In these formulations, histidine is a buffer agent, which can be used tomaintain the formulation pH from about pH 5.0 to about pH 6.5, or fromabout pH 5.5 to about pH 6.0, such as about pH 5.0, about pH 5.5, aboutpH 6.0, or about pH 6.5.

Sugars or sugar alcohol, such as mannitol, dextrose, glucose, trehalose,and/or sucrose, are used separately or in combination both ascryo-protectants and a stabilizer the anti-PRLR antibody in liquidformulations as well as during lyophilization.

Non-ionic surfactants such as polysorbates, including polysorbate 20 andpolysorbate 80; polyoxamers, including poloxamer 184 and 188; Pluronic®polyols; and other ethylene/polypropylene block polymers, stabilize theanti-PRLR antibody during processing and storage by reducing interfacialinteraction and prevent antibody from adsorption.

Arginine is a protein solubilizer and also a stabilizer that reducesantibody and other protein aggregation, such as anti-PRLR antibodyaggregation, and other possible degradation. Methionine is anantioxidant that prevents antibody oxidation during processing andstorage.

Sugars and inorganic salts are commonly used as protein stabilizers;however, both sugars and inorganic salts are also effective tonicityagents. If a formulation requires a high concentration of one or moresugars to stabilize an anti-PRLR antibody, the inorganic saltconcentration should be zero or kept very low in order to maintain theformulation's osmolality such that injection pain is reduced uponadministration.

As used herein, the term “salt” refers to inorganic salts, which includesodium chloride (NaCl), sodium sulfate (Na₂SO₄), sodium thiocyanate(NaSCN), magnesium chloride (MgCl), magnesium sulfate (MgSO₄), ammoniumthiocyanate (NH₄SCN), ammonium sulfate ((NH₄)₂SO₄), ammonium chloride(NH₄Cl), calcium chloride (CaCl₂), calcium sulfate (CaSO₄), zincchloride (ZnCl₂) and the like, or combinations thereof. The anti-PRLRantibody formulations disclosed herein are characterized by asubstantial absence of added salt and are, therefore, referred to hereinas salt-free antibody formulations. It will be understood by those ofskill in the art that the presence of inorganic salts within thepresently disclosed formulations that are introduced by pH adjustmentare not considered to be added salts. Such inorganic salts whenintroduced by pH adjustments, if present in a formulation according tothe present disclosure, should not exceed a concentration of about 2 mM.

As used herein, the term “surfactant” includes non-ionic surfactantsincluding, without limitation, polysorbates, such as polysorbate 20 or80, and the polyoxamers, such as poloxamer 184 or 188, Pluronic®polyols, and other ethylene/polypropylene block polymers. Amounts ofsurfactants effective to provide stable high concentration anti-PRLRantibody formulations are usually in the range of 50 ppm to 300 ppm. Theuse of non-ionic surfactants permits the formulations to be exposed toshear and surface stresses without causing denaturation of the anti-PRLRantibody, and also reduce the adsorption on the surfaces duringprocessing and storage. The formulations disclosed herein include,without limitation, formulations having one or more non-ionicsurfactant(s) including, for example, one or more polysorbate(s), suchas polysorbate 20 or 80; one or more polyoxamers, such as poloxamer 184or 188; Pluronic® polyols; and/or one or more ethylene/polypropyleneblock polymer(s). Exemplified herein are formulations having apolysorbate, such as polysorbate 20 (Tween® 20) or polysorbate 80(Tween® 80).

As used herein, the term “antibody” refers to a class of proteins thatare generally known as immunoglobulins Antibodies include full-lengthmonoclonal antibodies (mAb), such as IgG2 monoclonal antibodies, whichinclude immunoglobulin Fc regions. The term antibody also includesbispecific antibodies, diabodies, single-chain molecules, and antibodyfragments such as Fab, F(ab′)₂, and Fv.

As used herein, the term “anti-PRLR antibody” refers to an antibodyhaving binding specificity against the human PRLR protein as well asfragments and variants of the human PRLR protein. Anti-PRLR antibodiespresented herein can be IgG2 antibodies and include anti-PRLR IgG2monoclonal antibodies, such as chimeric, humanized, and fully-humananti-PRLR IgG2 monoclonal antibodies. Anti-PRLR monoclonal antibodies,including full-length antibodies and antigen binding fragments andvariants thereof, that are suitable for use in the formulationsdisclosed herein are presented in PCT Patent Publication NOs.WO/2011/069799, WO/2011/069798, WO/2011/069797, WO/2011/069796,WO/2011/069795, and WO/2011/069794, each of which are incorporated byreference herein in their entirety.

“Monoclonal antibodies” are characterized by having specificity for asingle antigenic determinant. Monoclonal antibodies can, for example, bemade by the hybridoma method described by Kohler and Milstein, Nature256:495 (1975) or by recombinant DNA methods such as those described inU.S. Pat. No. 4,816,567. Monoclonal antibodies can also be isolated fromphage display libraries using the techniques such as those described inClackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol.Biol. 222:581-597 (1991).

Monoclonal antibodies include “chimeric monoclonal antibodies” wherein aportion of a heavy and/or light chain includes sequences from antibodiesderived from one species, while the remainder of the antibody, includingthe Fc region, includes sequences from antibodies derived from a secondspecies, and the second species may be human. See, e.g., U.S. Pat. No.4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855(1984).

Monoclonal antibodies also include “humanized monoclonal antibodies”wherein one or more complementarity determining region (CDR) from aheavy and/or light chain sequence from antibodies derived from onespecies replace one or more CDR from a heavy and/or light chain sequencefrom antibodies derived from a second species, and the second speciesmay be human. The process of “humanization” is usually applied tomonoclonal antibodies developed for administration to humans. See, e.g.,Riechmann et al., Nature 332(6162):323-27 (1988) and Queen et al., Proc.Natl. Acad. Sci. USA 86(24):10029-33 (1989).

Monoclonal antibodies also include “fully-human monoclonal antibodies”wherein the entire heavy and light chain sequences are derived fromhuman antibody sequences. Fully-human monoclonal antibodies can begenerated by phage display technologies and can be isolated from micethat have been genetically engineered to express the human antibodyrepertoire. See, e.g., McCafferty et al., Nature 348(6301):552-554(1990), Marks et al., J. Mol. Biol. 222(3):581-597 (1991), and Carmenand Jermutus, Brief Funct. Genomic Proteomic 1(2):189-203 (2002).

As used herein, the term “Pharmaceutically effective amount” of ananti-PRLR antibody formulation refers to an amount of the formulationthat provides therapeutic effect in an administration regimen. The highconcentration anti-PRLR antibody formulations disclosed herein typicallyinclude an anti-PRLR antibody at a concentration ranging from about 1mg/ml to about 150 mg/ml, or from about 2 mg/ml to about 120 mg/ml, orfrom about 5 mg/ml to about 100 mg/ml, or from about 7.5 mg/ml to about60 mg/ml. Within some aspects the concentration of anti-PRLR antibodywithin these formulations is about 2 mg/ml, or about 7.5 mg/ml, or about20 mg/ml, or about 50 mg/ml, or about 60 mg/ml. Such formulations aretypically administered in a volume of less than about 2 ml, or about 1.5ml, or about 1 ml, or about 0.5 ml per injection site for subcutaneousinjection.

Within certain aspects, the anti-PRLR antibody formulation containsabout 30 mM histidine, about 100 ppm polysorbate 80, about 292 mMsucrose, about 20 mg/ml anti-PRLR antibody at a pH ranging from about pH5.0 to about pH 6.5. Within related aspects, the anti-PRLR antibodyformulation also contains from about 10 mM to about 50 mM arginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm polysorbate 80, about 234 mM sucrose,about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 toabout pH 6.5. Within related aspects, the anti-PRLR antibody formulationalso contains from about 30 mM to about 50 mM arginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm polysorbate 80, about 234 sucrose, about60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 to aboutpH 6.5. Within related aspects, the anti-PRLR antibody formulation alsocontains from about 30 mM to about 50 mM arginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm polysorbate 80, about 88 mM sucrose, about133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging fromabout pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 10 mM to about 50 mMarginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm polysorbate 20, about 88 mM sucrose, about133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH ranging fromabout pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 10 mM to about 50 mMarginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 200 ppm polysorbate 20, about 88 mM sucrose,about 133 mM glycine, about 60 mg/ml anti-PRLR antibody at a pH rangingfrom about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 10 mM to about 50 mMarginine.

Within other aspects, the anti-PRLR antibody formulation contains about70 mM histidine, about 80 ppm polysorbate 80, about 200 mM sucrose,about 60 mg/ml anti-PRLR antibody at a pH ranging from about pH 5.0 toabout pH 6.5. Within related aspects, the anti-PRLR antibody formulationalso contains from about 10 mM to about 50 mM arginine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm polysorbate 80, about 292 mM sucrose,about 10 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH rangingfrom about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 0 mM to about 10 mMmethionine.

Within other aspects, the anti-PRLR antibody formulation contains about70 mM histidine, about 80 ppm polysorbate 80, about 176 mM sucrose,about 133 mM glycine, about 30 mM lysine, about 60 mg/ml anti-PRLRantibody at a pH ranging from about pH 5.0 to about pH 6.5.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm about polysorbate 80, about 234 mMsucrose, about 30 mM arginine, about 60 mg/ml anti-PRLR antibody at a pHranging from about pH 5.0 to about pH 6.5. Within related aspects, theanti-PRLR antibody formulation also contains from about 0 mM to 10 mMmethionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm about polysorbate 80, about 234 mMsucrose, about 20 mM arginine, about 150 mg/ml anti-PRLR antibody at apH ranging from about pH 5.0 to about pH 6.5. Within related aspects,the anti-PRLR antibody formulation also contains from about 0 mM to 10mM methionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm about polysorbate 80, about 205 mMsucrose, about 20 mM arginine, about 60 mg/ml anti-PRLR antibody at a pHranging from about pH 5.0 to about pH 6.5. Within related aspects, theanti-PRLR antibody formulation also contains from about 0 mM to 10 mMmethionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm about polysorbate 80, about 205 mMsucrose, about 20 mM arginine, about 2 mg/ml anti-PRLR antibody at a pHranging from about pH 5.0 to about pH 6.5. Within related aspects, theanti-PRLR antibody formulation also contains from about 0 mM to 10 mMmethionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 80 ppm about polysorbate 80, about 205 sucrose,about 20 mM arginine, about 1 mg/ml anti-PRLR antibody at a pH rangingfrom about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 0 mM to 10 mM methionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm about polysorbate 80, about 205 trehalose,about 20 mM arginine, about 2 mg/ml anti-PRLR antibody at a pH rangingfrom about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 0 mM to 10 mM methionine.Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 75 ppm about polysorbate 80, about 205 trehalose,about 20 mM arginine, about 60 mg/ml anti-PRLR antibody at a pH rangingfrom about pH 5.0 to about pH 6.5. Within related aspects, the anti-PRLRantibody formulation also contains from about 0 mM to 10 mM methionine.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 234 mM sucrose, about 80 ppm polysorbate 80,about 30 mM arginine, about 5 mM methionine, about 7.5 mg/ml anti-PRLRantibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH5.5.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 234 mM sucrose, about 80 ppm polysorbate 80,about 30 mM arginine, about 5 mM methionine, about 60 mg/mL anti-PRLRantibody at a pH ranging from about pH 5.0 to about pH 6.5, such as pH5.5.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 234 mM sucrose, about 75 ppm Tween 80, about 30mM arginine, about 10 mM methionine, about 60 mg/mL anti-PRLR antibodyat a pH ranging from about pH 5.0 to about pH 6.5, such as pH 5.5.

Within other aspects, the anti-PRLR antibody formulation contains about10 mM histidine, about 263 mM sucrose, about 80 ppm polysorbate 80,about 60 mg/mL anti-PRLR antibody at a pH ranging from about pH 5.0 toabout pH 6.5, such as pH 6.0.

Thus, the present disclosure provides anti-PRLR mAb formulations,including anti-PRLR IgG2 mAb formulations, wherein the anti-PRLR mAb issoluble at high protein concentrations. The anti-PRLR mAb in theformulations disclosed herein remain soluble at concentrations ofbetween about 1 mg/ml to about 150 mg/ml and remain stable underisosmotic storage conditions and exhibit reduced viscosity as comparedto currently available antibody formulations.

The anti-PRLR antibody having a light chain comprising the amino acidsequence of SEQ ID NO: 1 and a heavy chain comprising the amino acidsequence of SEQ ID NO: 7 is an IgG2 antibody that blocks prolactinreceptor (PRLR). Anti-PRLR antibodies can prevent the onset orprogression of endometriosis by blocking PRLR, thereby overcomingdeficiencies in endometrial pathways. The high concentration, salt freeanti-PRLR antibody formulations presented herein can be administrated tothe patients via intravenous injection or subcutaneous injection orother injection routes.

As part of the present disclosure, stability of anti-PRLR antibodies isaffected by excipients. The stability of anti-PRLR antibody increaseswith the decrease of NaCl concentrations in the pH range defined. Inaddition, positively charged amino acids, such as arginine and lysine,can improve the stability anti-PRLR antibody and that pH greatly affectsanti-PRLR antibody aggregation. The aggregation of antibody solutionsincreases with increases in pH. The optimal pH for stabilizing theanti-PRLR antibodies presented herein ranges from about pH 5.0 to aboutpH 6.5 or from about pH 5.5 to about pH 6.0 such as about pH 5.0, aboutpH 5.5, about pH 6.0, or about pH 6.5.

Provided herein are anti-PRLR antibody formulations wherein theanti-PRLR antibodies include IgG2 antibodies, including human IgG2monoclonal anti-PRLR antibodies having a light chain sequence and aheavy chain sequence presented in one or more of PCT Patent PublicationNOs. WO/2011/069799, WO/2011/069798, WO/2011/069797 WO/2011/069796,WO/2011/069795, and WO/2011/069794.

Antibodies that may be suitably employed in the anti-PRLR antibodyformulations described herein are exemplified by the Mat3-hIgG2 antibodypresented in Table 1, which was obtained from the BioInvent PhageDisplay library (Lund, Sweden) and subsequently germlined andsequence-optimized for affinity, activity, species cross-reactivity, andmanufacturability.

The Fab part comprises a lambda light chain (VL: DPL3 germline; CL:Mcg-/Kern-/Oz-isotype) and a heavy chain VH DP47-germline frameworkregion. The antibody was reformatted into a human IgG2 of the IgG2m (n-)heavychain allotype lacking the C-terminal lysine. A potentialdeamidation site is present in CDR3 at amino acid position 98 of thelight chain and was left unchanged in this antibody. The standardN-glycosylation site of IgG2 is present at N294 of the heavy chain.

TABLE 1 Heavy and Light Chain Sequences of Exemplary HumanAnti-PRLR IgG2 Monoclonal Antibody Mat3-hIgG2 Sequence Portion ofAmino Acid Sequence Identifier Antibody Chain (NH₃—COOH) SEQ ID NO: 1Light Chain, QSVLTQPPSA SGTPGQRVTI Full-length SCTGSSSNIG AGYVVHWYQQLPGTAPKLLI YRNNQRPSGV PDRFSGSKSG TSASLAISGL RSEDEADYYC AAWDDSLNGWLFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPVKAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECSSEQ ID NO: 2 Light Chain, QSVLTQPPSA SGTPGQRVTI Variable DomainSCTGSSSNIG AGYVVHWYQQ LPGTAPKLLI YRNNQRPSGV PDRFSGSKSG TSASLAISGLRSEDEADYYC AAWDDSLNGW LFGGGTKLTV LGQ SEQ ID NO: 3 Light Chain,SCTGSSSNIG AGYVVH Variable Domain, CDR1 SEQ ID NO: 4 Light Chain,RNNQRPS Variable Domain, CDR2 SEQ ID NO: 5 Light Chain, CAAWDDSLNG WLVariable Domain, CDR3 SEQ ID NO: 6 Light Chain, PKAAPSVTLF PPSSEELQANConstant Domain KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQSNNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS SEQ ID NO: 7Heavy Chain, EVQLLESGGG LVQPGGSLRL Full-length SCAASGFTFS SYWMHWVRQAPGKGLEWVSD IARLSSYTNY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGLDARRMDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWNSGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSNFGTQTYT CNVDHKPSNT KVDKTVERKCCVECPPCPAP PVAGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV QFNWYVDGVEVHNAKTKPRE EQFNSTFRVV SVLTVVHQDW LNGKEYKCKV SNKGLPAPIE KTISKTKGQPREPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPMLDSDGSFFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG SEQ ID NO: 8Heavy Chain, EVQLLESGGG LVQPGGSLRL Variable Domain SCAASGFTFS SYWMHWVRQAPGKGLEWVSD IARLSSYTNY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGLDARRMDYWGQ GTLVTVSS SEQ ID NO: 9 Heavy Chain, FSSYWMHW Variable Domain,CDR1 SEQ ID NO: 10 Heavy Chain, SDIARLSSYT NYADSVKGR Variable Domain,CDR2 SEQ ID NO: 11 Heavy Chain, ARGLDARRMD Y Variable Domain, CDR3SEQ ID NO: 12 Heavy Chain, ASTKGPSVFP LAPCSRSTSE Constant DomainSTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQTYTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF LFPPKPKDTL MISRTPEVTCVVVDVSHEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTFR VVSVLTVVHQ DWLNGKEYKCKVSNKGLPAP IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEWESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPG

Thus, the present disclosure provides anti-PRLR mAb formulations,including anti-PRLR IgG2 mAb formulations, wherein the anti-PRLR mAb issoluble at high protein concentrations. Typically, the anti-PRLR mAb inthe formulations disclosed herein remain soluble at concentrations fromabout 1 mg/ml to about 150 mg/ml and remain stable under isosmoticstorage conditions and exhibit reduced viscosity as compared tocurrently available antibody formulations.

The anti-PRLR antibody having a light chain sequence and a heavy chainsequence presented in one or more of PCT Patent Publication NOs.WO/2011/069799, WO/2011/069798, WO/2011/069797, WO/2011/069796,WO/2011/069795, and WO/2011/069794 can be an IgG2 antibody that blocks aprolactin receptor activity. Anti-PRLR antibodies can prevent the onsetor progression of endometriosis by blocking PRLR, thereby overcomingdeficiencies in endometrial pathways. The wide protein concentrationrange, including high concentration anti-PRLR antibody formulationspresented herein can be administrated to the patients via intravenousinjection intramuscular injection or subcutaneous injection.

The present disclosure also provides methods for the non-hormonaltreatment of endometriosis in a patient, comprising the administrationto the patient of a therapeutically effective amount of one or moreformulations described herein. For example, provided are methods for thenon-hormonal treatment of endometriosis in a patient, comprising theadministration to the patient of a therapeutically effective amount ofan anti-prolactin receptor antibody (aPRLR Ab) formulation including anaPRLR-specific IgG2 monoclonal antibody (mAb) formulation that containsfrom about 0 mM to about 70 mM histidine; from about 50 ppm to about 300ppm polysorbate (Tween®) 80 and/or polysorbate (Tween®) 20; from about34 mM to about 292 mM sucrose; from about 0 mM to about 50 mM arginine,from about 0 mM to about 50 mM lysine, from about 0 mM to about 270 mMglycine or alanine, from about 0 mM to about 10 mM methionine, and fromabout 1 mg/ml to about 150 mg/ml of an anti-PRLR antibody at a pHranging from about pH 5.0 to about pH 6.5. Within at least one aspect ofthese methods, the anti-PRLR antibody formulation can be administeredintravenously. Within other aspects of these methods, the anti-PRLRantibody formulation can be administered subcutaneously. Within otheraspects of these methods, the anti-PRLR antibody formulation can beadministered intramuscularly.

According to certain aspects of these methods for the non-hormonaltreatment of endometriosis in a patient, the anti-PRLR antibody is ahuman anti-PRLR IgG2 monoclonal antibody such as, for example, a humananti-PRLR IgG2 monoclonal antibody that contains a light chain sequenceand a heavy chain sequence presented in one or more of PCT PatentPublication NOs. WO/2011/069799, WO/2011/069798, WO/2011/069797,WO/2011/069796, WO/2011/069795, and WO/2011/069794.

Aspects of the present disclosure may be further understood in light ofthe following examples, which should not be construed as limiting thescope of the present teachings in any way.

EXAMPLES Example 1 Effect of NaCl Concentration and pH on the Turbidityof Antibody Solutions

This Example discloses the effect of salt (NaCl) concentration and pH onthe aggregation of solutions containing an anti-PRLR human monoclonalantibody that contains a light chain sequence and a heavy chain sequencepresented in one or more of PCT Patent Publication Nos. WO/2011/069799,WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, andWO/2011/069794. The turbidity of solutions is assessed by visualobservation to quickly evaluate the effects of salt concentrations andpH on aPRLR mAb solutions. No precipitation is observed after 2 monthsat 5° C. and 25° C. with the formulation in absence of salt at pH5.5-6.5.

Solutions without sodium chloride at pH 5.0 to 6.5 are recommended forthe presently disclosed anti-PRLR antibody formulations.

Without being bound by theory, it is believed that the decreasedstability in terms of turbidity or aggregation of the anti-PRLR mAbformulations with high NaCl concentration results from theneutralization of positive charges on the anti-PRLR mAb arginineside-chains. The phase behavior of aPRLR mAb at different pH with theimpact of monovalent salt (NaCl) explains why the stable, soluble,non-salt, and substantial isosmolality aPRLR mAb formulations areachieved.

At a pH below the PI, such as pH 5-6.5, an anti-PRLR antibody has a netpositive charge. The repulsion of the positive charges on such ananti-PRLR antibody surface likely prevents protein-protein associationbetween individual molecules and, thereby, significantly increasessolubility. It is hypothesized that the anion (Cl⁻) of salt binds to theguanidinium group on arginine side-chains on an anti-PRLR antibodysurface to neutralize the positive charges, which enhancesprotein-protein interactions and, hence, causes lower solubility andsolution turbidity. By shifting the pH to 5.0-6.5, the non-saltformulations that are described herein are developed to achieveincreased antibody solubility and stability. In absence of salt, theconcentration of other stabilizers, such as sucrose, can be increasedto >150 mM and <300 mM without compromising osmolality.

Example 2 Anti-PRLR Antibody Formulations

Substantially isosmotic high concentration anti-PRLR Ab formulations areprepared without NaCl. These formulations employ high sucroseconcentrations to help stabilize the anti-PRLR Ab.

Frozen anti-PRLR antibody is thawed and formulated according toformulations presented in Table 2. The formulations are prepared and aresterile filtered with a 0.22 lam filter and sterile filled in glasstubing vials and stoppered with rubber stoppers.

In the absence of NaCl, and in the presence of sucrose or trehalose 34mM to 292 mM and polysobate 80 (50-300 ppm), and at pH 5.0-6.5, thepositive charged amino acids, such as arginine (10-50 mM), caneffectively inhibit aPRLR Ab from aggregation.

TABLE 2 Anti-PRLR Antibody Formulations 1 mg/ml aPRLR Ab 1 mg/ml aPRLRAb 10 mM histidine 205 mM sucrose 75 ppm polysorbate 80 20 mM arginine10 mM methionine pH 5.5 2 mg/ml aPRLR Ab 2 mg/ml aPRLR Ab 2 mg/ml aPRLRAb 10 mM histidine 10 mM histidine 234 mM sucrose 234 mM sucrose 75 ppmpolysorbate 80 75 ppm polysorbate 80 30 mM arginine 30 mM arginine 10 mMmethionine 10 mM methionine pH 5.5 pH 5.0 7.5 mg/ml aPRLR Ab 7.5 mg/mlaPRLR Ab 10 mM histidine 234 mM sucrose 80 ppm polysorbate 80 30 mMarginine 5 mM methionine pH 5.5 20 mg/ml aPRLR Ab 20 mg/ml aPRLR Ab 20mg/ml aPRLR Ab 20 mg/ml aPRLR Ab 30 mM histidine 30 mM histidine 30 mMhistidine 292 mM sucrose 292 mM sucrose 10% sucrose 60 ppm polysorbate80 60 ppm polysorbate 80 60 ppm polysorbate 80 pH 5.0 pH 5.5 pH 6.5 20mg/ml aPRLR Ab 30 mM histidine 292 mM sucrose 60 ppm polysorbate 80 50mM arginine pH 6.0 50 mg/ml aPRLR Ab 50 mg/ml aPRLR Ab 50 mg/ml aPRLR Ab10 mM histidine 10 mM histidine 234 mM sucrose 234 mM sucrose 75 ppmpolysorbate 80 75 ppm polysorbate 80 50 mM arginine 30 mM arginine pH at6 pH 5.5 60 mg/ml aPRLR Ab 60 mg/ml aPRLR Ab 60 mg/ml aPRLR Ab 60 mg/mlaPRLR Ab 10 mM histidine 10 mM histidine 10 mM histidine 234 mM sucrose88 mM sucrose 205 mM sucrose 75 ppm polysorbate 80 200 ppm polysorbate20 75 ppm polysorbate 80 pH 5.5 30 mM arginine 20 mM arginine 133 mMglycine 10 mM methionine pH at 5.5 pH 6.5 60 mg/ml aPRLR Ab 60 mg/mlaPRLR Ab 60 mg/ml aPRLR Ab 10 mM histidine 10 mM histidine 10 mMhistidine 234 mM sucrose 88 mM sucrose 205 mM trehalose 75 ppmpolysorbate 80 75 ppm polysorbate 80 75 ppm polysorbate 80 30 mMarginine 10 mM arginine 20 mM arginine pH 5.5 133 mM glycine 10 mMmethionine pH 5.5 pH 5.5 60 mg/ml aPRLR Ab 60 mg/ml aPRLR Ab 60 mg/mlaPRLR Ab 10 mM histidine 10 mM histidine 10 mM histidine 234 mM sucrose292 mM sucrose 205 mM trehalose 75 ppm polysorbate 80 75 ppm polysorbate80 75 ppm polysorbate 80 30 mM arginine 10 mM arginine 20 mM arginine pH6 10 mM methionine 10 mM methionine 133 mM glycine pH 5.5 pH 5.5 60mg/ml aPRLR Ab 60 mg/ml aPRLR Ab 60 mg/mL aPRLR Ab 10 mM histidine 10 mMhistidine 10 mM histidine 88 mM sucrose 388 mM sucrose 234 mM sucrose 75ppm polysorbate 80 75 ppm polysorbate 80 80 ppm polysorbate 80 30 mMarginine 30 mM lysine 30 mM arginine 133 mM glycine 133 mM glycine 5 mMmethionine pH 5.5 pH 5.5 pH 5.5 60 mg/ml aPRLR Ab 60 mg/ml aPRLR Ab 60mg/mL aPRLR Ab 10 mM histidine 10 mM histidine 10 mM histidine 88 mMsucrose 234 mM sucrose 234 mM sucrose 75 ppm polysorbate 20 75 ppmpolysorbate 80 75 ppm polysorbate 80 30 mM arginine 30 mM arginine 30 mMarginine 133 mM glycine 10 mM methionine 10 mM methionine pH 5.5 pH 5.5pH 5.5 60 mg/mL aPRLR Ab 60 mg/mL aPRLR Ab 60 mg/mL aPRLR Ab 70 mMhistidine 10 mM histidine 70 mM histidine 200 mM sucrose 263 mM sucrose176 mM sucrose 80 ppm polysorbate 80 80 ppm polysorbate 80 75 ppmpolysorbate 80 pH 6.0 pH 6.0 30 mM lysine pH 6.0 150 mg/ml aPRLR Ab 150mg/ml aPRLR Ab 10 mM histidine 234 mM sucrose 75 ppm polysorbate 80 30mM arginine 10 mM methionine pH 5.5

Representative anti-PRLR mAb formulations were analyzed by HPLC-SEC forprotein aggregation and degradation, LC-MS for aPRLR structural changes(glycation and oxidation), viscometer for viscosity measurement, andosmolality instrument for osmolality measurement. The results for theHPLC-SEC analysis of protein aggregation are presented in Table 3, theresults for the nephlometry analysis of turbidity are presented in Table4, the results for the LC-MS analysis of aPRLR structural changes arepresented in Table 5, and the results for the analysis of viscosity andosmolality are presented in Table 6.

TABLE 3 HPLC-SEC Average Rate of Aggregation Formation (%/day)Formulation Composition 5° C. 25° C. Anti-PRLR 60 mg/mL 0.000¹ 0.005¹Histidine 10 mM Sucrose 234 mM Polysorbate 80 75 ppm pH 5.5 Arginine 30mM Methionine 10 mM Anti-PRLR 60 mg/mL 0.013² 0.022² Histidine 10 mMSucrose 263 mM Polysorbate 80 80 ppm pH 6.0 ¹The calculation was basedon 100 days value. ²The calculation was based on 90 days value.

TABLE 4 LC-MS Results of the Formulations after Shaking at 100 rpm atRoom Temperature Formulation Composition Intact Mass Mass of LC and HCAnti-PRLR 60 mg/mL Comparable to RS¹ Comparable to RS¹ Histidine 10 mMSucrose 234 mM Polysorbate 75 ppm 80 pH 5.5 Arginine 30 mM Methionine 10mM Anti-PRLR 60 mg/mL Comparable to RS² Comparable to RS² Histidine 10mM Sucrose 263 mM Polysorbate 80 ppm 80 pH 6.0 ¹After the formulationwas shaken at 100 rpm at room temperature for 14 days. ²After theformulation was shaken at 100 rpm at room temperature for 21 days. LC =Light Chain; HC = Heavy Chain; RS = Reference Standard.

TABLE 5 Average Rate of Turbidity change (by Nephelometry) After Shakingat 100 rpm at Room Temperature Formulation Composition FNU/day Anti-PRLR60 mg/mL 0.643¹ Histidine 10 mM Sucrose 234 mM Polysorbate 80 75 ppm pH5.5 Arginine 30 mM Methionine 10 mM Anti-PRLR 60 mg/mL 0.013² Histidine10 mM Sucrose 263 mM Polysorbate 80 80 ppm pH 6.0 ¹After the formulationwas shaken at 100 rpm at room temperature for 14 days. ²After theformulation was shaken at 100 rpm at room temperature for 21 days.

TABLE 6 Viscosity and Osmolality of Anti-PRLR Ab Formulations Viscosity(mPa-S) at Osmolality Formulation Composition 22.0° C.-23.0° C.(mmol/kg) Anti-PRLR 60 mg/mL 1.83 342 Histidine 10 mM Sucrose 234 mMPolysorbate 80 80 ppm pH 5.5 Arginine 30 mM Methionine 5 mM Anti-PRLR 60mg/mL 2.37 345 Histidine 10 mM Sucrose 234 mM Polysorbate 80 75 ppm pH5.5 Arginine 30 mM Methionine 10 mM Anti-PRLR 60 mg/mL 2.17 299Histidine 10 mM Sucrose 263 mM Polysorbate 80 80 ppm pH 6.0

What is claimed is:
 1. An anti-PRLR antibody formulation, comprising: a.0 mM to 70 mM histidine; b. 50 ppm to 300 ppm of a non-ionic surfactant;c. 34 mM to 292 mM of a sugar selected from mannitol, dextrose, glucose,trehalose, and sucrose; d. 0 mM to 50 mM arginine; e. 0 mM to 50 mMlysine; f. 0 mM to 270 mM glycine or alanine; g. 0 mM to 10 mMmethionine; and h. 1 mg/ml to 150 mg/ml of an anti-PRLR antibody;wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0to pH 6.5.
 2. The anti-PRLR antibody formulation of claim 1 wherein saidanti-PRLR formulation contains substantially no inorganic salt otherthan an organic salt or an inorganic salt that buffers said formulation.3. The anti-PRLR antibody formulation of claim 1 wherein said anti-PRLRformulation contains substantially no inorganic salt selected from thegroup consisting of sodium chloride (NaCl), sodium sulfate (Na₂SO₄),sodium thiocyanate (NaSCN), magnesium chloride (MgCl), magnesium sulfate(MgSO₄), ammonium thiocyanate (NH₄SCN), ammonium sulfate ((NH₄)₂SO₄),ammonium chloride (NH₄Cl), calcium chloride (CaCl₂), calcium sulfate(CaSO₄), and zinc chloride (ZnCl₂).
 4. The anti-PRLR antibodyformulation of claim 1 wherein said formulation has a viscosity rangingfrom 1 to 8 mPa-S at 22° C.-23° C.
 5. The anti-PRLR antibody formulationof claim 1 wherein said formulation has and osmolality ranging from 240to 380 mmol/kg.
 6. The anti-PRLR antibody formulation of any of claim 1wherein said non-ionic surfactant is a polysorbate selected frompolysorbate 20 and polysorbate
 80. 7. The anti-PRLR antibody formulationof claim 1 wherein said sugar is sucrose or trehalose.
 8. The anti-PRLRantibody formulation of claim 1 comprising between 10 mM and 50 mMarginine.
 9. The anti-PRLR antibody formulation of claim 1, comprising:a. 30 mM histidine, b. 100 ppm polysorbate 80, c. 292 mM sucrose, and d.20 mg/ml anti-PRLR antibody; wherein said anti-PRLR antibody formulationhas a pH ranging from pH 5.0 to pH 6.5.
 10. The anti-PRLR antibodyformulation of claim 1, comprising: a. 10 mM histidine, b. 80 ppmpolysorbate 80, c. 234 mM sucrose, d. 60 mg/ml anti-PRLR antibody;wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0to pH 6.0.
 11. The anti-PRLR antibody formulation of claim 1,comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c. 234 mMsucrose, and d. 60 mg/ml anti-PRLR antibody; wherein said anti-PRLRantibody formulation has a pH ranging from pH 5.0 to pH 6.5.
 12. Theanti-PRLR antibody formulation of claim 1, comprising: a. 10 mMhistidine, b. 75 ppm polysorbate 80, c. 88 mM sucrose, d. 270 mMglycine, and e. 60 mg/ml anti-PRLR antibody; wherein said anti-PRLRantibody formulation has a pH ranging from pH 5.0 to pH 6.5.
 13. Theanti-PRLR antibody formulation of claim 1, comprising: a. 10 mMhistidine, b. 75 ppm polysorbate 20, c. 88 mM sucrose, d. 133 mMglycine, and e. 60 mg/ml anti-PRLR antibody; wherein said anti-PRLRantibody formulation has a pH ranging from pH 5.0 to pH 6.5.
 14. Theanti-PRLR antibody formulation of claim 1, comprising: a. 10 mMhistidine, b. 200 ppm polysorbate 20, c. 88 mM sucrose, d. 133 mMglycine, and e. 60 mg/ml anti-PRLR antibody; wherein said anti-PRLRantibody formulation has a pH ranging from pH 5.0 to pH 6.5.
 15. Theanti-PRLR antibody formulation of claim 1, comprising: a. 70 mMhistidine, b. 80 ppm polysorbate 80, c. 200 mM sucrose, and d. 60 mg/mlanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 16. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c.292 mM sucrose, d. 10 mM arginine, and e. 60 mg/ml anti-PRLR antibody;wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0to pH 6.5.
 17. The anti-PRLR antibody formulation of claim 1,comprising: a. 70 mM histidine, b. 75 ppm polysorbate 80, c. 176 mMsucrose, d. 30 mM lysine, and e. 60 mg/ml anti-PRLR antibody; whereinsaid anti-PRLR antibody formulation has a pH ranging from pH 5.0 to pH6.5.
 18. The anti-PRLR antibody formulation of claim 1, comprising: a.10 mM histidine, b. 75 ppm polysorbate 80, c. 234 mM sucrose, d. 30 mMarginine, and e. 10 mM methionine, and f. 60 mg/ml anti-PRLR antibody;wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0to pH 6.5.
 19. The anti-PRLR antibody formulation of claim 1,comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c. 234 mMsucrose, d. 30 mM arginine, and e. 10 mM methionine, and f. 2 mg/mlanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 20. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c.234 mM sucrose, d. 20 mM arginine, and e. 10 mM methionine, and f. 150mg/ml anti-PRLR antibody; wherein said anti-PRLR antibody formulationhas a pH ranging from pH 5.0 to pH 6.5.
 21. The anti-PRLR antibodyformulation of claim 1, comprising: a. 10 mM histidine, b. 75 ppmpolysorbate 80, c. 205 mM sucrose, d. 20 mM arginine, e. 10 mMmethionine, and f. 1 mg/ml anti-PRLR antibody; wherein said anti-PRLRantibody formulation has a pH ranging from pH 5.0 to pH 6.5.
 22. Theanti-PRLR antibody formulation of claim 1, comprising: a. 10 mMhistidine, b. 80 ppm polysorbate 80, c. 205 mM sucrose, d. 20 mMarginine, and e. 10 mM methionine, and f. 60 mg/ml anti-PRLR antibody;wherein said anti-PRLR antibody formulation has a pH ranging from pH 5.0to pH 6.5.
 23. The anti-PRLR antibody formulation of claim 1,comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c. 205 mMtrehlose, d. 20 mM arginine, and e. 10 mM methionine, and f. 60 mg/mlanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 24. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 75 ppm polysorbate 80, c.205 mM trehalose, d. 30 mM arginine, e. 10 mM methionine, and f. 2 mg/mlanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 25. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 234 mM sucrose, c. 80 ppmpolysorbate 80, d. 30 mM arginine, e. 5 mM methionine, and f. 7.5 mg/mlanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 26. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 234 mM sucrose, c. 80 ppmpolysorbate 80, d. 30 mM arginine, e. 5 mM methionine, and f. 60 mg/mLanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 27. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 234 mM sucrose, c. 75 ppmpolysorbate 80, d. 30 mM arginine, e. 10 mM methionine, and f. 60 mg/mLanti-PRLR antibody; wherein said anti-PRLR antibody formulation has a pHranging from pH 5.0 to pH 6.5.
 28. The anti-PRLR antibody formulation ofclaim 1, comprising: a. 10 mM histidine, b. 263 mM sucrose, c. 80 ppmpolysorbate 80, and d. 60 mg/mL anti-PRLR antibody; wherein saidanti-PRLR antibody formulation has a pH ranging from pH 5.0 to pH 6.5.29. The anti-PRLR antibody formulation of claim 1 wherein said anti-PRLRantibody is a human IgG2 monoclonal antibody.
 30. The anti-PRLR antibodyformulation of claim 29 wherein said human IgG2 monoclonal antibodycomprises a light chain sequence and a heavy chain sequence presented inone or more of PCT Patent Publication NOs. WO/2011/069799,WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, andWO/2011/069794.
 31. The anti-PRLR antibody formulation of claim 29wherein said human IgG2 monoclonal antibody comprises a light chainsequence of SEQ ID NO: 1 and a heavy chain sequence of SEQ ID NO:
 7. 32.A method for the non-hormonal treatment of endometriosis in a patient,said method comprising administering to said patient a therapeuticallyeffective amount of an anti-PRLR antibody formulation comprising between0 mM and 70 mM histidine, between 50 ppm and 200 ppm polysorbate 80 orpolysorbate 20, between 34 mM and 292 mM sucrose or trehalose, between 0mM and 50 mM arginine, between 0 mM and 50 mM lysine, between 0 mM and270 mM glycine or alanine, between 0 mM and 10 mM methionine, andbetween 1 mg/ml and 150 mg/ml of a protein or antibody at a pH ofbetween pH 5.0 and pH 6.5, wherein said anti-PRLR antibody formulationcontains substantially no inorganic salt.
 33. The method of claim 32wherein said anti-PRLR antibody formulation is administeredintravenously, subcutaneously, or intramuscularly.
 34. The method ofclaim 33 wherein said anti-PRLR antibody is a human IgG2 monoclonalantibody.
 35. The method of claim 34 wherein said human IgG2 monoclonalantibody comprises a light chain sequence and a heavy chain sequencepresented in one or more of PCT Patent Publication NOs. WO/2011/069799,WO/2011/069798, WO/2011/069797, WO/2011/069796, WO/2011/069795, andWO/2011/069794.
 36. The method of claim 15 wherein said human IgG2monoclonal antibody comprises a light chain sequence of SEQ ID NO: 1 anda heavy chain sequence of SEQ ID NO: 7.